A fibroblast growth factor receptor (FGFR) is one kind of a receptor tyrosine kinase, and as a ligand of FGFR, a fibroblast growth factor (FGF) has been known. In the FGFR family, the presence of four receptor types, that is, an FGFR1, an FGFR2, an FGFR3 and an FGFR4 has been known. The receptors are made up of a transmembrane protein having an extracellular domain, a transmembrane domain and a cytoplasmic domain. The extracellular domain includes two or three immunoglobulin (Ig) domains. FGFR is a monomeric tyrosine kinase receptor, which is activated by dimerization which occurs on a cell surface in a complex of an FGFR dimer, an FGF, and a heparin glycan or a proteoglycan. For the FGF, 22 kinds of known FGFs are present, and each has an ability to bind to one or a plurality of FGFRs. FGF binds to FGFR, and thereby the receptor tyrosine kinase is activated, and a signal transduction is carried out downstream. Depending on difference in site or period of FGFR expression, complicated biological functions such as a cell migration and a cell proliferation are controlled.
Among the FGFR family, in a FGFR4 gene of human, three human splicing variants (FGFR4 gene variant 1 (GenBank Accession number: NM—002011.3), variant 2 (GenBank Accession number: NM—022963.2) and variant 3 (GenBank Accession number: NM—213647.1)) have been known so far. Among these, the variant 1 and the variant 3 encode an isoform 1 of FGFR4, and the variant 2 encodes an isoform 2 of FGFR4. The FGFR4 isoform 1 is consisting of full length 802 amino acids, and the isoform 2 is consisting of full length 762 amino acids. The isoform 1 and the isoform 2 have a different amino acid sequence in a region in the transmembrane domain, and have the same amino acid sequence in an extracellular domain and a cytoplasmic domain.
It is confirmed that a tyrosine kinase domain of FGFR is present in the cytoplasmic domain, and in various cancers, a point mutation in the tyrosine kinase domain of FGFR is related to activation of cancer. It has been reported that among these, for FGFR4 in rhabdomyoma, an amino acid mutation (N535K, N535D) was found at position 535 in the isoform 1, an introduction of these point mutations causes a constitutive activation of FGFR4, cytoplasmic signals are abnormally activated, and thereby causing canceration and a cell proliferation (Non-Patent Document 1).
However, it has not been reported that an activating point mutation other than the N535K mutation and the N535D mutation is present in the tyrosine kinase domain of FGFR4.